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Mirtazapine

A Review of its Use in Major Depression and Other Psychiatric Disorders

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Summary

Abstract

Mirtazapine (Remeron®, Zispin®) is a noradrenergic and specific serotonergic antidepressant (NaSSA) that is approved in many counties for use in the treatment of major depression. Monotherapy with mirtazapine 15—45mg/day leads to rapid and sustained improvements in depressive symptoms in patients with major depression, including the elderly. It is as effective as other antidepressants and may have a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs). Furthermore, it may also have a higher sustained remission rate than amitriptyline. Preliminary data suggest that mirtazapine may also be effective in the treatment of anxiety disorders (including post-traumatic stress disorder, panic disorder and social anxiety disorder), obsessive-compulsive disorder, undifferentiated somatoform disorder and, as add-on therapy, in schizophrenia, although large, well designed trials are needed to confirm these findings. Mirtazapine is generally well tolerated in patients with depression. In conclusion, mirtazapine is an effective antidepressant for the treatment of major depression and also has the potential to be of use in other psychiatric indications.

Pharmacological Properties

The antidepressant activity of mirtazapine, an NaSSA agent, is thought to result from a combination of noradrenergic and serotonergic effects, with the latter specifically involving enhancement of serotonin 5-HT1 receptor-mediated effects. It acts as an antagonist at central α2-adrenergic autoreceptors and heteroreceptors, andpostsynaptic 5-HT2 and 5-HT3 receptors. Mirtazapine has low affinity for central and peripheral dopaminergic receptors, but is a potent antagonist of histamine H1 receptors and a moderate antagonist at muscarinic receptors. Mirtazapine improves sleep efficiency and continuity, and does not suppress rapid eye movement sleep.

Mirtazapine is absorbed rapidly after oral administration, with peak plasma concentrations achieved within 2 hours. Food has no clinically relevant effect on absorption. Mirtazapine displays linear pharmacokinetics over the therapeutic dosage range, and steady state is reached after ≈5 days. Mirtazapine is extensively metabolized, principally via cytochrome P450 (CYP) isoenzymes CYP3A4, CYP2D6 and CYP1A2. The elimination half-life of mirtazapine is 20—40 hours. Mirtazapine is a racemate and the enantiomers display differing pharmacokinetic and pharmacodynamic properties; both enantiomers contribute to the pharmacodynamic effects of mirtazapine.

Therapeutic Efficacy

A number of well designed trials have demonstrated the efficacy of mirtazapine in the treatment of patients with moderate to severe major depression. Mirtazapine was more effective than placebo at relieving the symptoms of depression in short-term studies and effectively prevented relapse for up to 1 year. In short-term comparisons with tricyclic antidepressants (TCAs) and related drugs, mirtazapine howed antidepressant efficacy similar to that of comparator agents such as amitriptyline and trazodone. The proportion of patients classified as Hamilton Depression Rating Scale (HAM-D) responders in comparisons with amitriptyline ranged from 53% to 72% with mirtazapine and from 48% to 72% with amitriptyline. Mirtazapine also had a higher sustained remission rate than amitriptyline in a long-term, double-blind continuation study. In comparisons with trazodone, HAM-D response rates were 51—61% with mirtazapine and 41—51% with trazodone. In comparisons with SSRIs over 6—24 weeks, mirtazapine showed similar anti-depressant efficacy to citalopram (single study), fluoxetine, paroxetine and sertra-line (single study). Overall, the proportion of patients classified as HAM-D responders at endpoint in these trials was 50—73% for mirtazapine, 45—71% forfluoxetine, 50—56% for paroxetine and 52% for sertraline (HAM-D response data not available for citalopram). Mirtazapine was as effective as venlafaxine in the treatment of hospitalized patients with severe depression with melancholic features.

In a meta-analysis comparing 12 newer-generation antidepressants, mirtazapine emerged as one of four agents deemed to have superior efficacy in the acute-phase treatment of major depression. Other meta-analyses of trials comparing mirtazapine with SSRIs found that mirtazapine was associated with an earlier onset of action than SSRIs.

The efficacy of mirtazapine has been demonstrated in patients treated in hospital, outpatient and primary care settings. Efficacy has been shown in elderly patients, patients who have not responded to SSRIs and in those with symptoms of anxiety or insomnia.

A number of smaller trials (n < 100) have also shown promising results with mirtazapine in other psychiatric disorders, including post-stroke depression, post-traumatic stress disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, undifferentiated somatoform disorder and (as add-on therapy) in schizophrenia. Other small studies showed promising results with mirtazapine in patients with major depression and concomitant conditions such as Parkinson’s disease, cancer or fibromyalgia syndrome.

Tolerability

Mirtazapine was generally well tolerated in clinical trials in patients with major depression. Events occurring at a significantly higher incidence with mirtazapine than with placebo included drowsiness, excessive sedation, increased appetite, weight gain and dry mouth. The pattern of adverse events in elderly patients was similar to that in the overall population. At therapeutic doses, mirtazapine had no significant effect on blood pressure or heart rate and had a low potential for inducing seizures. Mirtazapine generally had no adverse effects on sexual function, and switching patients with SSRI-induced sexual dysfunction to mirtazapine improved sexual function. Compared with TCAs and trazodone, mirtazapine was generally associated with a lower incidence of dizziness, tremor and anticholinergic adverse events. Compared with SSRIs, mirtazapine was associated with less insomnia and nausea, but with more weight gain, dry mouth, fatigue and excessive somnolence.

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Authors and Affiliations

  1. Wolters Kluwer Health ∣ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Katherine F. Croom, Caroline M. Perry & Greg L. Plosker

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Katherine F. Croom, Caroline M. Perry & Greg L. Plosker

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  1. Katherine F. Croom
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  2. Caroline M. Perry
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  3. Greg L. Plosker
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Correspondence to Greg L. Plosker.

Additional information

Various sections of the manuscript reviewed by: I. Anghelescu, Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Berlin, Germany; J. Ishigooka, Department of Psychiatry, Tokyo Women’s Medical University, Tokyo, Japan; S. Kasper, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; C-U. Pae, Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea; T. Suzuki, School of Medicine, Department of Neuropsychiatry, Keio University, Tokyo, Japan; S-J. Tsai, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; H. Uchida, School of Medicine, Department of Neuropsychiatry, Keio University, Tokyo, Japan.

Data Selection Sources: Medical literature published in any language since 1980 on ‘mirtazapine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health j Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search term was Various sections of the manuscript reviewed by: ‘mirtazapine’. Searches were last updated 2 April 2009.

Selection: Studies in patients with depression or other psychiatric disorders who received mirtazapine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Mirtazapine, depression, psychiatric disorders, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Croom, K.F., Perry, C.M. & Plosker, G.L. Mirtazapine. CNS Drugs 23, 427–452 (2009). https://doi.org/10.2165/00023210-200923050-00006

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